The Role of M6A in HOTAIR Targeting and Induced Heterochromatin Formation in Breast Cancer
Abstract
Each cell in our bodies contains the same genetic information (DNA). Yet specific genes get “transcribed” into messenger RNA (mRNA) molecules that will be “translated” into proteins with specific cellular functions to make up the different cells and tissues in our body with diverse functions. For instance, normal breast cells, like many other epithelial cells that line glands in our bodies, are designed to secrete substances into ducts (in breast the ultimate function is to secrete milk for nutrition for newborn offspring). In cancer, dysregulation of gene expression programs can contribute to cells not functioning properly and moving around to places in the body where they should not go (metastasis). In addition to genes that encode proteins, many noncoding DNA sequences are also transcribed into RNA molecules, and these noncoding RNAs can act to dictate when and where mRNA molecules get turned on or off. Noncoding RNA molecules are often expressed at higher levels than normal in cancer cells, which contribute to their pathogenesis. My work focuses on HOTAIR, a long noncoding RNA (lncRNA) that is frequently elevated in several types of cancers. Patients with cancers that have high levels of HOTAIR tend to have worse outcomes. HOTAIR overexpression causes different genes to turn on and off and increases metastasis of cancer cells. However, it is unclear how HOTAIR targets specific genes for regulation. Our lab recently discovered a mechanism in which a protein that binds RNA specifically binds HOTAIR and directs it to specific places on the DNA. This same protein can read a specific mark on RNA called N6-methyladenosine (m6A). Mapping sites that contain m6A marks revealed that HOTAIR mRNA targets are enriched for this mark. In this proposal, I will investigate how m6A on mRNA targets impacts the recruitment of HOTAIR to target genes, which we term “matchmaking.” This proposal uses molecular biology to understand how matchmaking and the m6A modification lead to gene regulation. Using a novel platform and quantitative proteomics, I will identify proteins involved in the HOTAIR machinery and will determine how the m6A modification interacts with the HOTAIR pathway. Elucidating the molecular mechanism of HOTAIR-induced gene regulation could enable novel therapeutic treatments for breast cancer and possibly other types of cancers. My long-term career goals include establishing an independent research program studying molecular mechanisms that lead to metastasis of breast cancer. Ultimately, I hope to provide insight that leads to treatments that could prevent metastasis and mortality of breast cancer. My researcher development plan will enable me to make advances in our understanding of mechanisms of HOTAIR-induced breast cancer metastasis in a unique training environment under the supervision of Drs. Aaron Johnson and Jennifer Richer. With the combination of their experience in biochemical studies of mechanisms of chromatin regulation and breast cancer progression of these mentors, as well as the community of breast cancer researchers at the Anschutz Medical Campus, I will have an excellent training environment to enable my transition to an independent research career that aims to prevent breast cancer-related mortality. This research on the RNA modification m6A and its role in HOTAIR-mediated gene repression aims to elucidate the mechanism of HOTAIR-induced metastasis of breast cancer and reveal new therapeutic targets to treat metastasis and ultimately to prevent recurrence of and mortality due to breast cancer. The RNA-centric nature of this work has potential clinical advantages, as these molecules can be targeted with drugs already approved by the Food and Drug Administration (FDA) including oligonucleotides to reduce expression of target RNAs. Ultimately, the identification of molecular mechanisms that contribute to breast cancer metastasis will improve our understanding of how it can be preven
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810023
Entities
People
- Allison Porman
Organizations
- United States Army
- University of Colorado Denver